The purpose of this proposal is to cultivate the scientific development and advance the research skills of Dr. Chad Boomershine so that he may become an independent investigator. Dr. Boomershine is currently developing his academic career in the Physician-Scientist Training Program at Vanderbilt University Medical Center (VUMC). VUMC provides an environment conducive to developing physician-scientists through its many laboratory resources, educational opportunities, and expert faculty. Under the guidance of Drs. Timothy Blackwell and James W. Thomas, Dr. Boomershine will design and perform experiments that will enhance his knowledge and research skills in the pathobiology of autoimmune pancreatitis (AIP). Through laboratory experience and formal coursework, he will gain expertise in experimental design and execution, transgenic murine model development, cellular and molecular biology techniques, statistical analysis, and reporting of results. These skills will provide the foundation for Dr. Boomershine to pursue an independent academic career in AIP research. AIP is a chronic form of pancreatitis in humans caused by loss of immune tolerance to pancreatic antigens that can result in death due to destruction of exocrine pancreatic tissue. In preliminary data, we describe an innovative animal model of AIP in transgenic mice lacking the ability to respond to transforming growth factor [unreadable] (TGF[unreadable]) in S100A4 expressing cells. For this proposal, we have formed the following hypothesis: TGF[unreadable] signaling maintains immunologic tolerance by regulating S100A4 positive dendritic cells (DCs), and deficient TGF[unreadable] signaling in the presence of NF/cB activation leads to persistence of activated DCs and development of AIP. To test this hypothesis, we have developed the following specific aims: 1) to characterize the role of S100A4 positive DCs in the development of AIP;2) to define mechanisms by which S100A4 positive DCs regulate immune activation;and 3) to investigate the importance NF?B signaling plays in the maturation of S100A4 positive DCs in the development of AIP. Autoimmune disease is a common phenomenon that occurs in every organ system. Up to 23.5 million Americans have an autoimmune disease and the prevalence is rising. Since a breakdown in immune tolerance underlies the pathogenesis of all autoimmune diseases, knowledge gained through study of AIP could identify new therapeutic targets for the treatment of not only AIP but other autoimmune disorders.